Estrogen receptor α AF-2 mutation results in antagonist reversal and reveals tissue selective function of estrogen receptor modulators

Arao, Yukitomo; Hamilton, Katherine; Ray, Manas K.; Scott, Gregory J.; Mishina, Yuji; Korach, Kenneth S.

doi:10.1073/pnas.1109180108

Cited by 81 publications

(140 citation statements)

References 43 publications

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“…In the present study, the tissue-specific effects of E2, the estrogen antagonist ICI, and two SERMs were evaluated using a mouse model lacking ERαAF-2. The evaluated estrogen-responsive parameters are all known to be mediated via ERα, and we confirmed our previous study demonstrating that all these ERα-mediated effects of E2 require ERαAF-2 (12,13,22). Recently, Arao et al (22) generated an AF-2 mutated ERα knock-in (AF2ERKI) mouse model, which has L543A and L544A aa mutations in the AF-2 region of H12 of ERα.…”

Section: Ici Acts As An Erα Agonist On Trabecular Bone Mass and Uterusupporting

confidence: 63%

“…In the present study, we used the ERαAF-2 0 mouse model with a specific inactivation of AF-2 in ERα as a result of deletion of aa 543-549 (12). Similar to the short-term ICI treatment of AF2ERKI mice in the study by Arao et al (22), long-term ICI treatment of ERαAF-2 0 mice, in the present study, resulted in a uterine response, confirming that ICI acts as an ERα agonist in the uterus of mice with mutations/deletions of ERαAF-2. The main phenotypes evaluated in the present study were skeletal, including trabecular bone, cortical bone, and growth plate parameters.…”

Section: Ici Acts As An Erα Agonist On Trabecular Bone Mass and Uterumentioning

confidence: 99%

“…A recent in vivo study demonstrated that ICI acts as an ERα agonist in the uteri of mice with mutations in the ERα AF-2, supporting the concept of a crucial role of ERα AF-2 for ligand activity (22). To in vivo evaluate the tissue-dependent effects of ICI on several estrogen-responsive parameters, ovariectomized (ovx) wild-type (WT) mice and mice lacking the entire ERαAF-2 (ERαAF-2 0 ) were treated with ICI, E2, or vehicle (Veh).…”

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confidence: 98%

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The estrogen receptor antagonist ICI 182,780 can act both as an agonist and an inverse agonist when estrogen receptor α AF-2 is modified

Movérare‐Skrtic

Börjesson

Farman

et al. 2014

Proc. Natl. Acad. Sci. U.S.A.

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Significance Estrogen exerts important effects in the skeleton, which are primarily mediated via estrogen receptor (ER)α, which stimulates target gene transcription through two activation functions (AFs), AF-1 in the N-terminal and AF-2 in the ligand-binding domain. Previous studies demonstrate that ERα ligands might act as agonists, partial agonists, or antagonists. We demonstrate that the ERα antagonist ICI 182,780 (ICI) acts in a tissue-dependent manner in mice lacking ERαAF-2, resulting in no effect, agonistic activity, or inverse agonistic activity. Importantly, ICI exerted a pronounced inverse agonistic activity in the growth plate of mice lacking ERαAF-2. We propose that ERα lacking AF-2 is constitutively active in the absence of ligand in the growth plate, enabling ICI to act as an inverse agonist.

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Section: Ici Acts As An Erα Agonist On Trabecular Bone Mass and Uterusupporting

confidence: 63%

Section: Ici Acts As An Erα Agonist On Trabecular Bone Mass and Uterumentioning

confidence: 99%

mentioning

confidence: 98%

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The estrogen receptor antagonist ICI 182,780 can act both as an agonist and an inverse agonist when estrogen receptor α AF-2 is modified

Movérare‐Skrtic

Börjesson

Farman

et al. 2014

Proc. Natl. Acad. Sci. U.S.A.

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“…The ligand-induced activation of ERa involves the actions of distinct AFs, which contributes to the ERa activity depending on the cell type and promoter context (26,29,30). Indeed, it has been recently shown using AF targeted mice that ERa AF-1 mediated physiological responses in certain tissues but was dispensable in others (33)(34)(35)42). Using similar validated models, we now establish that the E2-mediated effects on GM-or FL-DC development and effector functions are mediated through ERa AF-1-independent or -dependent mechanisms, respectively.…”

Section: Discussionmentioning

confidence: 99%

Estradiol Promotes Functional Responses in Inflammatory and Steady-State Dendritic Cells through Differential Requirement for Activation Function-1 of Estrogen Receptor α

Seillet

Rouquié

Foulon

et al. 2013

The Journal of Immunology

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17β-Estradiol (E2) has been shown to regulate GM-CSF– or Flt3 ligand–driven dendritic cell (DC) development through estrogen receptor (ER) α signaling in myeloid progenitors. ERα regulates transcription of target genes through two distinct activation functions (AFs), AF-1 and AF-2, whose respective involvement varies in a cell type– or tissue-specific manner. In this study, we investigated the role of ERα AFs in the development and effector functions of inflammatory DCs, steady-state conventional DCs, and plasmacytoid DCs (pDC), using mouse lacking either AF-1 or AF-2. In agreement with previous works, we showed that E2 fostered the differentiation and effector functions of inflammatory DCs through ERα-dependent upregulation of IFN regulatory factor (IRF)-4 in GM-CSF–stimulated myeloid progenitors. Interestingly, whereas AF-1 was required for early IRF-4 upregulation in DC precursors, it was dispensable to enhance IRF-4 expression in differentiated DCs to a level compatible with the development of the more functional Ly6C− CD11b+ DC subset. Presence of E2 had no effect on progenitors from either knock-in mice with 7-aa deletion in helix 12 of ERα, lacking AF-2, or ERα−/− mice. By contrast, in Flt3 ligand–driven DC differentiation, activation of AF-1 domain was required to promote the development of more functionally competent conventional DCs and pDCs. Moreover, lack of ERα AF-1 blunted the TLR7-mediated IFN-α response of female pDCs in vivo. Thus, our study demonstrates that ERα uses AF-1 differently in steady-state and inflammatory DC lineages to regulate their innate functions, suggesting that selective ER modulators could be used to target specific DC subsets.

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“…The roles of the activation functions of ERα have been studied in vivo using mice deleted for ERαAF-1 or ERαAF-2 (3)(4)(5). These results, in particular the two models of ERαAF-2 inactivation (4,6), suggested that many physiological functions strongly rely on nuclear ERα and gene transcription regulation. However, in addition to the nuclear, termed "genomic actions of ER," the receptors stimulate rapid (from seconds to minutes), nonnuclear signal transduction, usually termed "nongenomic" or "extranuclear" effects.…”

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confidence: 98%

Mutation of the palmitoylation site of estrogen receptor α in vivo reveals tissue-specific roles for membrane versus nuclear actions

Adlanmérini

Solinhac

Abot

et al. 2013

Proc. Natl. Acad. Sci. U.S.A.

229

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Estrogen receptor alpha (ERα) activation functions AF-1 and AF-2 classically mediate gene transcription in response to estradiol (E2). A fraction of ERα is targeted to plasma membrane and elicits membrane-initiated steroid signaling (MISS), but the physiological roles of MISS in vivo are poorly understood. We therefore generated a mouse with a point mutation of the palmitoylation site of ERα (C451A-ERα) to obtain membrane-specific loss of function of ERα. The abrogation of membrane localization of ERα in vivo was confirmed in primary hepatocytes, and it resulted in female infertility with abnormal ovaries lacking corpora lutea and increase in luteinizing hormone levels. In contrast, E2 action in the uterus was preserved in C451A-ERα mice and endometrial epithelial proliferation was similar to wild type. However, E2 vascular actions such as rapid dilatation, acceleration of endothelial repair, and endothelial NO synthase phosphorylation were abrogated in C451A-ERα mice. A complementary mutant mouse lacking the transactivation function AF-2 of ERα (ERα-AF2 0 ) provided selective loss of function of nuclear ERα actions. In ERα-AF2 0 , the acceleration of endothelial repair in response to estrogen-dendrimer conjugate, which is a membrane-selective ER ligand, was unaltered, demonstrating integrity of MISS actions. In genome-wide analysis of uterine gene expression, the vast majority of E2-dependent gene regulation was abrogated in ERα-AF2 0 , whereas in C451A-ERα it was nearly fully preserved, indicating that membrane-to-nuclear receptor cross-talk in vivo is modest in the uterus. Thus, this work genetically segregated membrane versus nuclear actions of a steroid hormone receptor and demonstrated their in vivo tissuespecific roles.fertility | vascular effects | nongenomic effects | genomic actions A lthough estrogens classically serve as reproductive hormones, they induce cellular responses in almost all tissues in mammalian species. The biological effects of estrogens, and particularly of 17β-estradiol (E2), are initiated by their binding to intracellular estrogen receptors (ERs), ERα and ERβ, which classically serve as nuclear transcription factors (1, 2). The ERs regulate the transcription of hundreds of genes in a cell-and tissue-specific manner through their two activation functions (AFs), AF-1 and AF-2. The roles of the activation functions of ERα have been studied in vivo using mice deleted for ERαAF-1 or ERαAF-2 (3-5). These results, in particular the two models of ERαAF-2 inactivation (4, 6), suggested that many physiological functions strongly rely on nuclear ERα and gene transcription regulation. However, in addition to the nuclear, termed "genomic actions of ER," the receptors stimulate rapid (from seconds to minutes), nonnuclear signal transduction, usually termed "nongenomic" or "extranuclear" effects. The rapid mobilization of intracellular calcium and the generation of cAMP by E2 were demonstrated several decades ago (7,8). More recently, the modulation of potassium currents, phospholipase C activatio...

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Estrogen receptor α AF-2 mutation results in antagonist reversal and reveals tissue selective function of estrogen receptor modulators

Cited by 81 publications

References 43 publications

The estrogen receptor antagonist ICI 182,780 can act both as an agonist and an inverse agonist when estrogen receptor α AF-2 is modified

The estrogen receptor antagonist ICI 182,780 can act both as an agonist and an inverse agonist when estrogen receptor α AF-2 is modified

Estradiol Promotes Functional Responses in Inflammatory and Steady-State Dendritic Cells through Differential Requirement for Activation Function-1 of Estrogen Receptor α

Mutation of the palmitoylation site of estrogen receptor α in vivo reveals tissue-specific roles for membrane versus nuclear actions

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